Characterization of D-amino acids in colostral, transitional, and mature preterm human milk.

D-Amino acids are regulatory molecules that affect biological processes. Therefore, being able to accurately detect and quantify these compounds is important for understanding their impact on nutrition and health. There is a paucity of information regarding D-amino acids in human milk. We developed a fast method for simultaneous analysis of amino acid enantiomers in human milk using liquid chromatography with tandem mass spectrometry. The method enables the separation of 41 amino acids without chemical derivatization. Our results revealed that human milk from mothers of preterm infants contains concentrations of D-amino acids that range from 0.5 to 45% that of their L-counterparts and that levels of most D-amino acids decrease as the milk production matures. Moreover, we found that Holder pasteurization of milk does not cause racemization of L-amino acids. To our knowledge, this is the first study to describe percentages of D-amino acid levels in human milk; changes in D-amino acid concentration as the milk matures; and the effect of Holder pasteurization on D- and L-amino acid concentrations in human milk.

Galectin-4 as a Novel Biomarker of Neonatal Intestinal Injury.

BACKGROUND: Neonates are at risk of gastrointestinal emergencies including necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP). Identifying biomarkers to aid in diagnosis is imperative. We hypothesized that circulating intestinal-specific protein concentrations would distinguish infants with intestinal injury from controls. AIMS: To identify serum concentrations of intestinal-specific protein(s) in infants with intestinal injury and controls. METHODS: We used an in silico approach to identify intestinal-specific proteins. We collected serum from control infants and infants with NEC or SIP and measured protein concentrations using ELISA. If baseline concentrations were near the detection limit in initial control assays, we proceeded to assess concentrations in a larger cohort of controls and infants with injury. Control infants were frequency matched to infants with injury and compared with nonparametric and mixed-effects models analysis. RESULTS: We evaluated four proteins with high intestinal expression: Galectin-4 (Gal-4), S100G, Trefoil Factor-3, and alanyl aminopeptidase. Only Gal-4 demonstrated consistent results near the lower limit of quantification in controls and was studied in the larger cohorts. Gal-4 concentration was low in 111 control infants (median 0.012 ng/ml). By contrast, Gal-4 was significantly increased at diagnosis in infants with surgical NEC and SIP (n = 14, p ≤ 0.001 and n = 8, p = 0.031) compared to matched controls, but not in infants with medical NEC (n = 32, p = 0.10). CONCLUSIONS: Of the intestinal-specific proteins evaluated, circulating Gal-4 concentrations were at the assay detection limit in control infants. Gal-4 concentrations were significantly elevated in infants with surgical NEC or SIP, suggesting that Gal-4 may serve as a biomarker for neonatal intestinal injury.

Normative values for circulating intestinal fatty acid binding protein and calprotectin across gestational ages.

BACKGROUND: Necrotizing enterocolitis (NEC) is associated with significant morbidity and mortality. Serum biomarkers to aid diagnosis, such as intestinal fatty acid binding protein (IFABP) and calprotectin, are actively being investigated; however, the normative values of these markers among healthy premature and term infants remains unknown. We sought to identify normative values for the serum concentrations of IFABP and calprotectin across gestational (GA) and post-menstrual age. METHODS: We collected serum from infants (24-40 weeks GA) in the first week of life and at multiple time points in a sub-cohort of premature infants (24-29 weeks GA), excluding sepsis or known intestinal disease. IFABP and calprotectin were measured using ELISA. Groups were compared with descriptive statistics and mixed effects linear regression. RESULTS: One hundred twelve infants had specimens in the first week of life, and 19 premature infants had longitudinal specimens. IFABP concentration in the first week of life was low and did not differ across gestational ages. Longitudinally, IFABP increased 4% per day (P < 0.001). Calprotectin concentration in the first week of life was more variable. An inverse relationship between day of life and calprotectin level was found in the longitudinal cohort (P < 0.001). CONCLUSIONS: Serum IFABP and calprotectin fluctuate over time. Infants had low levels of IFABP during the first week of life, independent of gestational age, and levels increased longitudinally in premature infants. Calprotectin levels generally declined over time. Normative data for infants is necessary to establish meaningful cut-off levels for clinical use.

Respiratory Compliance in Late Preterm Infants (340/7-346/7 Weeks) after Antenatal Steroid Therapy.

OBJECTIVE: To compare respiratory compliance in late preterm infants (340/7-346/7 weeks) who received antenatal steroids vs matched late preterm infants who did not receive antenatal steroids. STUDY DESIGN: This was a single-center prospective cohort study. Patients were matched for birth weight, gestational age, race, and sex. Respiratory compliance was the primary outcome measured with the single breath occlusion technique. RESULTS: We studied 25 late preterm infants treated with antenatal steroids and 25 matched infants who did not receive antenatal steroids. The treated infants had a significantly increased respiratory compliance/kg (adjusted 95% CI 0.05, 0.49; P = .016) and fewer required continuous positive airway pressure (P = .007) or >24 hours of supplemental oxygen (P = .046). There was no difference in surfactant therapy. CONCLUSIONS: Respiratory compliance was significantly increased in this cohort of late preterm infants born at 340/7-346/7 weeks who received antenatal steroids compared with matched infants who did not receive antenatal steroids. Although not randomized, these data provide physiologic support for the possible beneficial effects of antenatal steroids in late preterm infants.

Rehospitalization in Infants Born < 29 Weeks' Gestation during the First 2 Years of Life: Risk Assessment.

OBJECTIVE: This study aims to determine risk factors for rehospitalization in extremely premature infants. STUDY DESIGN: A retrospective cohort study of 157 infants born < 29 weeks' gestational age assessing risk factors for rehospitalization through 2 years of life. RESULTS: Multivariable logistic regression showed that an increasing number of respiratory infections (odds ratio [OR]: 1.8 [1.1-3.1] per infection p = 0.03) and inhaled steroid use at 1 year (OR: 4.0 [1.3-12.1] p = 0.01) were predictive of hospital readmission. Diuretic (OR: 27 [1.01-1,000] p = 0.04) and oxygen (OR: 32 [3.1-333] p = 0.004) use at 1 year were predictive of pediatric intensive care unit admission. The number of respiratory infections (OR: 2.8 [1.7-4.5] p < 0.0001) with reflux/aspiration necessitating G-tube/Nissen fundoplication surgical intervention with or without G-tubes alone (OR: 21.3 [2.9-166.7] p = 0.02 and OR: 22.7 [CI, 2.4-200] p = 0.04) was predictive of increased number of rehospitalizations. CONCLUSIONS: Key modifiable risk factors identified were reflux/aspiration and ongoing respiratory infections. Critical time periods for diuretic, oxygen, and inhaled steroid use in this population occurred at the age of 1 year.

Vitamin C supplementation for pregnant smoking women and pulmonary function in their newborn infants: a randomized clinical trial.

IMPORTANCE: Maternal smoking during pregnancy adversely affects offspring lung development, with lifelong decreases in pulmonary function and increased asthma risk. In a primate model, vitamin C blocked some of the in-utero effects of nicotine on lung development and offspring pulmonary function. OBJECTIVE: To determine if newborns of pregnant smokers randomized to receive daily vitamin C would have improved results of pulmonary function tests (PFTs) and decreased wheezing compared with those randomized to placebo. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind trial conducted in 3 sites in the Pacific Northwest between March 2007 and January 2011. One hundred fifty-nine newborns of randomized pregnant smokers (76 vitamin C treated and 83 placebo treated) and 76 newborns of pregnant nonsmokers were studied with newborn PFTs. Follow-up assessment including wheezing was assessed through age 1 year, and PFTs were performed at age 1 year. INTERVENTIONS: Pregnant women were randomized to receive vitamin C (500 mg/d) (n = 89) or placebo (n = 90). MAIN OUTCOMES AND MEASURES: The primary outcome was measurement of newborn pulmonary function (ratio of the time to peak tidal expiratory flow to expiratory time [TPTEF:TE] and passive respiratory compliance per kilogram [Crs/kg]) within 72 hours of age. Secondary outcomes included incidence of wheezing through age 1 year and PFT results at age 1 year. A subgroup of pregnant smokers and nonsmokers had genotyping performed. RESULTS: Newborns of women randomized to vitamin C (n = 76), compared with those randomized to placebo (n = 83), had improved pulmonary function as measured by TPTEF:TE (0.383 vs 0.345 [adjusted 95% CI for difference, 0.011-0.062]; P = .006) and Crs/kg (1.32 vs 1.20 mL/cm H2O/kg [95% CI, 0.02-0.20]; P = .01). Offspring of women randomized to vitamin C had significantly decreased wheezing through age 1 year (15/70 [21%] vs 31/77 [40%]; relative risk, 0.56 [95% CI, 0.33-0.95]; P = .03). There were no significant differences in the 1-year PFT results between the vitamin C and placebo groups. The effect of maternal smoking on newborn lung function was associated with maternal genotype for the α5 nicotinic receptor (rs16969968) (P < .001 for interaction). CONCLUSIONS AND RELEVANCE: Supplemental vitamin C taken by pregnant smokers improved newborn PFT results and decreased wheezing through 1 year in the offspring. Vitamin C in pregnant smokers may be an inexpensive and simple approach to decrease the effects of smoking in pregnancy on newborn pulmonary function and respiratory morbidities. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00632476.

Late preterm antenatal steroid use and infant outcomes in a single center.

OBJECTIVE: To characterize late preterm antenatal steroids (AS) use and associated neonatal outcomes in a single academic center. STUDY DESIGN: Retrospective study of 503 singleton, mother-infant dyads delivered between 34 0/7 and 36 6/7 weeks gestation between January 1, 2016 and December 31, 2020. RESULTS: Forty-three percent did not receive AS (No AS) prior to delivery. Among AS treated, 50% were sub-optimal dosing. No AS had higher preterm premature rupture of membranes and maternal diabetes. AS group had lower mean gestational age, birthweight, longer time from admission to delivery and longer NICU stay. There was no difference in neonatal hypoglycemia. CONCLUSIONS: Sub-optimal AS dosing in late preterms remains high in our center. AS did not improve neonatal outcomes. Studies are needed to evaluate the impact of AS in diabetics delivering late preterm, to optimize the timing of AS dosing, and evaluate the longer term impact on late preterm infants.

Late Preterm Antenatal Steroid Use and Infant Outcomes in a Single Center.

Objective: To characterize late preterm antenatal steroids (AS) use and associated neonatal outcomes in a single academic center. Study Design: Retrospective study of 503 singleton, mother-infant dyads delivered between 34 0/7 to 36 6/7 weeks gestation between January 1, 2016 to December 31, 2020. Results: 43% did not receive AS (No AS) prior to delivery. Among AS treated, 50% were sub-optimal dosing. No AS had higher preterm premature rupture of membranes and maternal diabetes. AS group had lower mean gestational age and birthweight and longer time from admission to delivery and longer NICU study. There was no difference in neonatal hypoglycemia. Conclusions: Sub-optimal AS dosing in late preterms remains high in our center. AS did not improve neonatal outcomes. Studies are needed to evaluate the impact of AS in diabetics delivering late preterm, to optimize the timing of AS dosing, and evaluate the longer term impact on late preterm infants.

Premature monochorionic monoamniotic twins have lower lung compliance at birth than matched dichorionic diamniotic twins.

BACKGROUND: Premature infants are born with immature lungs that demonstrate abnormal pulmonary function with differences in passive respiratory system compliance and resistance, and functional residual capacity. To our knowledge, no studies have evaluated differences in neonatal pulmonary function based on the type of twin gestation, or chorionicity. Given the effect of chorionicity on outcomes, we aimed to study the effect of twin type, monochorionic monoamniotic (MCMA) vs dichorionic diamniotic (DCDA), on neonatal early pulmonary function tests. METHODS: In this prospective cohort study, 5 sets of DCDA twins were matched to 5 sets of MCMA twins on gestational age at delivery, latency from antenatal corticosteroid exposure, birthweight, race and gender. Mean values were compared for passive respiratory system compliance and resistance, functional residual capacity, and tidal volume. RESULTS: MCMA infants had a significantly lower compliance (0.64 vs 1.25 mL/cm H2O /kg; p = 0.0001) and significantly higher resistance (0.130 vs 0.087 cm H2O /mL/sec; p = 0.0003) than DCDA infants. Functional residual capacity was lower for MCMA than DCDA infants (17.5 vs 23.4 mL/kg; p = 0.17). Further, 80% of MCMA infants required intubation for surfactant administration compared to 20% of DCDA infants, indicating the clinical significance of these objective measures. CONCLUSIONS: Due to the matched case-control design, causality cannot be established. However, we speculate that these differences in lung function may derive from differential exposure to preterm labor and endogenous maternal corticosteroid exposure. Further study is necessary to establish the true causal relationship.

Pulmonary function in extremely low birth weight infants with bronchopulmonary dysplasia before hospital discharge.

OBJECTIVE: To compare pulmonary function in extremely low birth weight (ELBW) infants with bronchopulmonary dysplasia (BPD) studied at 34-36 weeks postmenstrual age (PMA) with a reference group of "healthy" infants born at 34-36 weeks. We hypothesized that ELBW infants have decreased functional residual capacity (FRC) and respiratory compliance (Crs). STUDY DESIGN: Pulmonary function testing was performed at 34-36 weeks PMA in infants with BPD and within 96 h of age in infants delivered at 34-36 weeks. RESULTS: Twenty BPD patients and 20 healthy infants were studied. FRC (18.9 versus 26.2 mL/kg; adjusted 95% CI 5.0, 10.9; P < 0.001) and Crs (0.80 versus 1.29-mL/cm H2O/kg; 95% CI 0.31, 0.71; P < 0.001) were decreased in BPD patients. Respiratory resistance was increased in BPD patients. CONCLUSIONS: ELBW infants with BPD have decreased pulmonary function compared to healthy infants delivered at 34-36 weeks. This suggests that infants with BPD have smaller lung volumes.

Hair and nail nicotine levels of mothers and their infants as valid biomarkers of exposure to intrauterine tobacco smoke.

INTRODUCTION: Tobacco use remains the single most modifiable cause of adverse pregnancy outcomes. It is crucial to be able to accurately quantify the burden of tobacco exposure on both the mother and fetus to have better measures of efficacy with interventions being studied. METHODS: This is a descriptive and exploratory study conducted within a randomized controlled trial. Pregnant smoking and non-smoking women were followed from ≤22 weeks' gestation through delivery with monthly maternal smoking questionnaires, urine cotinine levels, and collection of maternal and infant hair and nail samples, at delivery. Nicotine was extracted and measured (ng/mg) using high-performance liquid chromatography with electrochemical detection. RESULTS: Forty-six mother-infant dyads (34 pregnant smokers and 12 pregnant non-smokers) had successful completion of maternal and infant hair and nails samples. The median hair nicotine levels of the smoking mothers and their infants was significantly higher than those of the non-smokers (1.015 vs 0.037 ng/ mg, p<0.05 for the mothers; 0.445 vs 0.080 ng/mg, p<0.01 for the infants). Similarly, the median nail nicotine levels for smoking mothers and their infants were significantly higher than the non-smokers (2.130 vs 0.056 ng/mg, p<0.01 for the mothers; 0.594 vs 0.132 ng/mg, p<0.05 for the infants). We found a moderate but significant correlation between maternal hair and nail nicotine (r=0.64, p<0.001), infant hair and nail nicotine (r=0.64; p<0.001), maternal and infant hair nicotine (r=0.61, p<0.001), and maternal and infant nail nicotine levels (r=0.58, p<0.001). CONCLUSIONS: Our study shows that both infant hair and nail nicotine levels are valid biomarkers of intrauterine tobacco smoke exposure, and can be used to identify prenatal smoke exposure, correlating well with the level of maternal nicotine exposure.

Fetal and neonatal morbidity and mortality following delivery after previous cesarean.

This article examines data from a recent systematic evidence review on term deliveries conducted for the National Institutes of Health Consensus Conference sponsored by the Agency for Healthcare Research and Quality on vaginal birth after caesarean, from a meta-analysis of associated perinatal outcomes, and subsequent publications that meet stringent quality review standards. We present a summary of fetal and neonatal outcomes emphasizing information that clinicians and patients need to make decisions regarding mode of delivery after prior cesarean and look for areas where future studies may provide important insights.

Increased vitamin E intake is associated with higher alpha-tocopherol concentration in the maternal circulation but higher alpha-carboxyethyl hydroxychroman concentration in the fetal circulation.

BACKGROUND: The transfer of vitamin E across the placenta is limited, but no data exist on the concentrations of vitamin E metabolites carboxyethyl hydroxychromans (α- and γ-CEHCs) in the fetal circulation. OBJECTIVE: We measured α- and γ-CEHC concentrations in maternal and umbilical cord blood pairs and examined their relations to circulating vitamin E (α- and γ-tocopherol) and maternal dietary vitamin E intake. DESIGN: Healthy, pregnant women were enrolled from Oregon Health and Science University's obstetric clinic (<22 wk gestation), and at least one fasting blood sample and a previous day's 24-h diet recall were collected during their pregnancy (n = 19). Umbilical cord blood samples were obtained at the time of delivery and were analyzed for α- and γ-tocopherol, α- and γ-CEHC, and total lipid concentrations. RESULTS: Mean (±SD) concentrations of umbilical cord blood α-CEHC (30.2 ± 28.9 nmol/L) and γ-CEHC (104.5 ± 61.3 nmol/L) were not significantly different from maternal concentrations (P = 0.07 and 0.08, respectively), but metabolite:tocopherol ratios were significantly higher in cord blood (P < 0.01 and 0.001, respectively). Maternal α-tocopherol:total lipids ratios were correlated with cord blood α-CEHCs (r = 0.67, P = 0.004), and higher vitamin E intakes were associated with higher cord blood α-CEHC concentrations (r = 0.75, P < 0.003). CONCLUSION: Higher maternal intake of vitamin E during pregnancy may result in increased metabolite concentrations in the fetal circulation, suggesting increased maternal or fetal liver metabolism of vitamin E. This trial was registered at clinicaltrials.gov as NCT00632476.